News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2019)

Because adherence to as-needed short-acting β-agonists and daily maintenance inhaled corticosteroids (ICSs) in patients with mild intermittent asthma is often poor, Jo Hardy et al (Lancet 2019; https://doi.org/10.1016/S0140-6736(19)31948-8) examined the real-world efficacy of as-needed monotherapy with a single inhaler containing an ICS and a long-acting β-agonist. Use of as-needed budesonide-formoterol decreased the number of severe exacerbations while decreasing overall steroid exposure compared with a daily maintenance ICS plus an as-needed short-acting β-agonist (terbutaline). Importantly, these findings support the recommendation made by the 2019 Global Initiative for Asthma advocating the use of ICS-formoterol reliever therapy as an alternative treatment to daily ICSs in patients with mild asthma.Use of as-needed budesonide-formoterol decreased the number of severe exacerbations Use of as-needed budesonide-formoterol decreased the number of severe exacerbations We asked senior author Richard Beasley, MBChB, DM, DSc, of the Medical Research Institute of New Zealand, Newtown, Wellington, New Zealand, to comment on the article. He writes, “These findings suggest that the timing of ICS administration is a more important determinant of efficacy than the total ICS dose and that titrating the ICS dose through the vehicle of symptom-driven bronchodilator use in patients with worsening asthma might lead to resolution of an exacerbation before it becomes severe enough for the patient to seek medical review.” Altman et al (J Clin Invest 2019; https://doi.org/10.1172/JCI126402) have discovered that type 2 inflammation and airway hyperresponsiveness (AHR) in asthmatic patients are closely related to a shift in the physical location of mast cells from the submucosa to the airway epithelium. Furthermore, the authors identified that the proallergic, epithelium-derived cytokine IL-33 enhances type 2 cytokine release from mast cells and that mast cells increased epithelial IL33 expression in a feedforward loop. Notably, this feedforward loop was enhanced in primary epithelial cells derived from patients with asthma. Collectively, these results demonstrate that mast cells that shift to the epithelium can regulate AHR and type 2 cytokine production and that IL-33 signaling through mast cells mediates a novel feedforward loop that regulates epithelial IL33 expression and might serve as a therapeutic target in the treatment of asthma.AHR results from type 2 cytokine–induced mast cell infiltration AHR results from type 2 cytokine–induced mast cell infiltration We asked senior author Teal S. Hallstrand, MD, MPH, of the University of Washington, Seattle, Washington, to comment on the article. He writes, “AHR is a central feature of asthma and a dominant cause of asthma symptoms in the majority of patients with asthma who experience episodes of asthma-related symptoms in response to triggers, such as exercise in cold dry air. Our study reveals that a shift in mast cells to the epithelium is closely related to these features of asthma and that mast cells have the capacity to regulate type 2 inflammation produced by mast cells and other innate cells by altering levels of epithelial IL33 expression.” The recent IMPACT trial demonstrated a reduction in chronic obstructive pulmonary disease (COPD) exacerbations with use of single-inhaler triple therapy (inhaled corticosteroid [ICS], long-acting muscarinic antagonist, and long-acting β-agonist [LABA]) compared with ICS-LABA or long-acting muscarinic antagonist–LABA combinations. In a subsequent analysis of this trial, Pascoe et al (Lancet Respir Med 2019;7:745-56; https://doi.org/10.1016/S2213-2600(19)30190-0) have identified that ICSs exerted a greater therapeutic effect in patients with greater blood eosinophil counts. Notably, this finding was observed in both former and current smokers, with the greatest benefit present in former smokers. In total, these findings show that blood eosinophil counts and smoking status are useful biomarkers in predicting response to ICS-containing therapies in patients with COPD. We asked first author Stephen Pascoe, MBBS, MS, of GlaxoSmithKline, Collegeville, Pennsylvania, to comment on the article. He writes, “Our work has prospectively replicated our original hypothesis of the importance of blood eosinophils and smoking as a significant predictor of the response to ICSs in patients with COPD, which has now been incorporated into treatment guidelines. More work is required to build on the use of these and other markers as tools in the advancement of precision medicine in the treatment of COPD.” Charcot-Leyden crystals (CLCs) are eosinophil-derived self-aggregates of the protein galectin-10 and are a hallmark of severe eosinophilic inflammation. Persson et al (Science 2019;364; https://doi.org/10.1126/science.aaw4295) have elucidated an important role for CLCs in stimulating type 2 immunity. Exogenous administration of galectin-10 crystals, but not a soluble mutant form, induced innate and adaptive immune responses and acted as a type 2 adjuvant. The authors generated novel antibodies that dissolved CLCs and reversed hallmark disease features in an experimental murine model of asthma. These findings illustrate an important proinflammatory role for CLCs in asthmatic patients and suggest CLC-dissolving antibodies as a novel therapeutic strategy for patients with severe eosinophilic inflammation. Figure attribution: Public Domain at Wikimedia Commons by user Yale Rosen [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)]. Induced innate and adaptive immune responses and acted as a type 2 adjuvant Induced innate and adaptive immune responses and acted as a type 2 adjuvant Follicular helper T (TFH) cells allow for IgE synthesis by inducing B-cell isotype switching through cytokine release. Gowthaman et al (Science 2019;365; https://doi.org/10.1126/science.aaw6433) have characterized a rare TFH cell population, termed TFH13 cells, that induces production of high-affinity IgE through production of both IL-4 and IL-13. Notably, TFH13 cells were only present in conditions in which high-affinity IgE was made, including during sensitization to food allergens or aeroallergens but not during infection. Additionally, elimination of TFH13 cells or of the ability of TFH cells to produce IL-13 impaired production of high-affinity IgE responses. In summation, the authors have identified a novel TFH subset that drives production of anaphylactic IgE and represents a novel therapeutic target for preventing anaphylaxis. We asked senior authors Adam Williams, PhD, of The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut and Stephanie Eisenbarth, MD, PhD, of Yale University, New Haven, Connecticut, to comment on the article. They write, “We are particularly interested in understanding how allergens drive development of TFH13 cells. If we can manipulate this step, we could potentially prevent allergic responses from developing.”News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.